JP7748209B2 - Oral pharmaceutical compositions and tablet compositions - Google Patents

Description

The present invention relates to an oral pharmaceutical composition and a tablet composition containing itopride and/or a salt thereof. More specifically, the present invention relates to an oral pharmaceutical composition in which the bitterness of itopride and/or a salt thereof is reduced, and a tablet composition that can improve the hardness of tablets containing itopride and/or a salt thereof.

Itopride and its salts have an antagonistic effect on dopamine _D2 receptors present in the stomach and duodenum, and exhibit a gastrointestinal motility activating effect by liberating acetylcholine, and are therefore used to improve gastrointestinal symptoms (abdominal distension, upper abdominal pain, loss of appetite, heartburn, nausea, vomiting, etc.) associated with functional dyspepsia and chronic gastritis. Patent Document 1 also reports that itopride and its salts have the effect of treating and/or preventing gastrointestinal dysfunction during drug administration.

Itopride and its salts are said to have few side effects such as extrapyramidal symptoms due to dopamine _D2 receptor antagonism, lactation due to increased prolactin secretion, and gynecomastia, and are widely used in daily clinical practice.

Japanese Patent Application Laid-Open No. 2000-212091

Given that itopride and its salts have been widely used in routine clinical practice for many years, there is hope for their development into over-the-counter (OTC) drugs. If itopride and/or its salts can be used as the active ingredient in an over-the-counter (OTC) drug, it would be desirable to further combine it with other active gastrointestinal ingredients to create a combination gastrointestinal drug. Furthermore, it is desirable that combination gastrointestinal drugs containing itopride and/or its salts be formulations that offer high added value, rather than simply being a collection of active gastrointestinal ingredients.

First, itopride and its salts are known to have a distinctive bitter taste. This distinctive bitter taste of itopride and its salts is so strong that it cannot be improved even by adopting formulations for improving taste that are commonly used in pharmaceutical compositions. Therefore, the distinctive bitter taste of itopride and/or its salts causes stress when taking the drug and is a factor that leads to non-compliance.

The first object of the present invention is to provide an oral pharmaceutical composition that is a gastrointestinal combination drug containing itopride and/or its salts, in which the bitterness characteristic of itopride and/or its salts has been reduced.

Secondly, as a means of masking the taste of pharmaceutical compositions containing itopride and its salts and making them easier to take, it is possible to formulate them into tablets. However, forming them into tablets usually requires the use of a specific binder to impart hardness, and gastrointestinal medicines contain multiple active ingredients, leaving little room for binders. Therefore, there is a need for formulations that can improve the hardness of tablets containing itopride and its salts by means other than binders.

The second object of the present invention is to provide a tablet composition that is a combination pharmaceutical containing itopride and/or a salt thereof and that can be molded into tablets with improved hardness.

The present inventors conducted extensive research to solve the first problem and discovered that by further adding an antacid and/or an azulene derivative, which are active gastrointestinal ingredients, to an oral pharmaceutical composition containing itopride and/or a salt thereof, the bitterness of itopride and/or a salt thereof can be significantly improved, thereby improving the ease of administration.

Furthermore, the present inventors conducted extensive research to solve the second problem and discovered that by further adding methylmethionine sulfonium salt and/or aluminum hydroxide, which are active ingredients in gastrointestinal medicines, to a tablet composition containing itopride and/or a salt thereof, the hardness of the tablet formed into tablets is significantly improved.

The present invention has been completed through further investigation based on these findings. That is, the present invention provides the following aspects.
Item 1. An oral pharmaceutical composition comprising (A) itopride and/or a salt thereof, and (B) an antacid and/or (C) an azulene derivative.
Item 2. The oral pharmaceutical composition according to Item 1, wherein component (B) comprises a metal selected from the group consisting of aluminum, magnesium, sodium, and calcium.
Item 3. The oral pharmaceutical composition according to Item 1 or 2, comprising a total amount of 66 to 10,000 parts by weight of component (B) per 100 parts by weight of component (A).
Item 4. The oral pharmaceutical composition according to Item 1 or 2, comprising a total amount of 0.5 to 50 parts by weight of component (C) per 100 parts by weight of component (A).
Item 5. A method for reducing the bitterness of itopride and/or a salt thereof, comprising comprising adding (A) itopride and/or a salt thereof to an oral pharmaceutical composition, together with (B) an antacid and/or (C) an azulene derivative.
Item 6. A tablet composition containing (A) itopride and/or a salt thereof, and (D) a methylmethionine sulfonium salt and/or (E) aluminum hydroxide.
Item 7. The tablet composition according to Item 6, comprising a total amount of 5 to 500 parts by weight of component (D) per 100 parts by weight of component (A).
Item 8. The tablet composition according to Item 6 or 7, comprising a total amount of 500 to 5,000 parts by weight of component (E) per 100 parts by weight of component (A).
Item 9. A method for increasing the hardness of a tablet containing itopride and/or a salt thereof, wherein the tablet composition contains (A) itopride and/or a salt thereof together with (D) a methylmethionine sulfonium salt and/or (E) aluminum hydroxide.

The oral pharmaceutical composition of the present invention provides a gastrointestinal combination drug that effectively reduces the bitter taste characteristic of itopride and/or its salts and improves ease of administration by combining itopride and/or its salts with an antacid and/or an azulene derivative.

Furthermore, the tablet composition of the present invention uses itopride and/or a salt thereof in combination with methylmethionine sulfonium salt and/or aluminum hydroxide, thereby providing a complex gastrointestinal drug that can improve the hardness of tablets when formed into tablets.

1. Oral Pharmaceutical Composition The oral pharmaceutical composition of the present invention is characterized by containing itopride and/or a salt thereof (sometimes referred to as "ingredient (A)"), and an antacid (sometimes referred to as "ingredient (B)") and/or an azulene derivative (sometimes referred to as "ingredient (C)"). The oral pharmaceutical composition of the present invention is described in detail below.

[(A) Itopride and/or its salt]
The oral pharmaceutical composition of the present invention contains itopride and/or a salt thereof as component (A). Itopride is a known compound that acts on dopamine _D2 receptors to promote the release of acetylcholine and inhibit the degradation of acetylcholine, thereby activating gastrointestinal motility.

Salts of itopride are not particularly limited as long as they are pharmaceutically acceptable, but examples include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, maleate, fumarate, malate, citrate, oxalate, lactate, and tartrate. Of these salts, inorganic acid salts are preferred, and hydrochloride is more preferred.

In the oral pharmaceutical composition of the present invention, one type of itopride and its salts may be selected and used alone as component (A), or two or more types may be used in combination.

Of the components (A), salts of itopride are preferred, and itopride hydrochloride is more preferred.

The content of component (A) in the oral pharmaceutical composition of the present invention may, in principle, be set appropriately depending on the dosage form, dosage amount, etc., but may be, for example, 0.1 to 90% by weight. From the perspective of further enhancing the bitterness-reducing effect, the content of component (A) in the oral pharmaceutical composition of the present invention is preferably 0.1 to 30% by weight, more preferably 0.1 to 10% by weight, even more preferably 0.1 to 5% by weight, and even more preferably 0.1 to 3% by weight. Generally, the higher the content of itopride and/or a salt thereof, the more likely the characteristic bitterness is to be perceived upon administration. However, in the oral pharmaceutical composition of the present invention, bitterness can be effectively reduced even if the lower limit of the content range of component (A) is 1% by weight or more, 2% by weight or more, or 2.4% by weight or more.

More specifically, when the oral pharmaceutical composition of the present invention contains component (B), the content of component (A) may be appropriately set depending on the dosage form, dosage amount, etc., and may be, for example, 0.1 to 90% by weight. From the perspective of further enhancing the bitterness-reducing effect, when the oral pharmaceutical composition of the present invention contains component (B), the content of component (A) is preferably 0.1 to 30% by weight, more preferably 0.1 to 10% by weight, even more preferably 0.1 to 5% by weight, and even more preferably 0.1 to 3% by weight.

When the oral pharmaceutical composition of the present invention contains component (C), the content of component (A) may be appropriately determined depending on the dosage form, dosage amount, etc., and may be, for example, 50 to 99% by weight. From the perspective of further enhancing the bitterness-reducing effect, when the oral pharmaceutical composition of the present invention contains component (C), the content of component (A) is preferably 60 to 99% by weight, more preferably 70 to 99% by weight, even more preferably 80 to 98% by weight, and even more preferably 92 to 97% by weight.

[(B) Antacids]
The oral pharmaceutical composition of the present invention may contain an antacid as component (B). When itopride and/or a salt thereof is used in combination with an antacid, the bitter taste characteristic of itopride and/or a salt thereof can be effectively alleviated.

An antacid is a drug that neutralizes stomach acid. There are no particular limitations on the type of antacid used in the present invention, but examples include antacids containing a metal selected from the group consisting of aluminum, magnesium, sodium, and calcium.

Antacids containing aluminum include, but are not limited to, magnesium aluminometasilicate, magnesium aluminosilicate, synthetic aluminum silicate, aluminum sucrose sulfate, dried aluminum hydroxide gel, magnesium alumina hydroxide, aluminum hydroxide gel, synthetic hydrotalcite, dihydroaluminum aminoacetate, aluminum hydroxide/sodium bicarbonate co-precipitation product, aluminum hydroxide/magnesium carbonate mixed dried gel, aluminum hydroxide/magnesium carbonate co-precipitation product, dihydroxyaluminum aminoacetate, etc.

Antacids containing magnesium are not particularly limited, but examples include magnesium aluminometasilicate, magnesium alumina hydroxide, magnesium silicate, magnesium hydroxide, magnesium oxide, magnesium carbonate, synthetic hydrotalcite, aluminum hydroxide/magnesium carbonate mixed dry gel, and aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitation product.

Sodium-containing antacids are not particularly limited, but examples include sodium bicarbonate and aluminum hydroxide/sodium bicarbonate co-precipitation products.

Antacids containing calcium are not particularly limited, but examples include precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, squid bone, volcanic rock, volcanic ash, and aluminum hydroxide-magnesium carbonate-calcium carbonate co-precipitation products.

These antacids may be used alone or in combination of two or more.

Among the (B) components, from the viewpoint of further effectively enhancing the bitterness-reducing effect of itopride and/or its salts, preferred are antacids containing a metal selected from the group consisting of aluminum, magnesium, and sodium, more preferred are magnesium aluminometasilicate, synthetic hydrotalcite, magnesium hydroxide, and sodium bicarbonate, and even more preferred are synthetic hydrotalcite, magnesium aluminometasilicate, and sodium bicarbonate.

Furthermore, among the (B) components, from the viewpoint of more effectively improving the bitterness of itopride and/or its salts and/or improving the harsh taste, preferred antacids containing aluminum include magnesium aluminometasilicate, magnesium aluminosilicate, synthetic aluminum silicate, aluminum sucrose sulfate, dried aluminum hydroxide gel, magnesium alumina hydroxide, aluminum hydroxide gel, and synthetic hydrotalcite, more preferably magnesium aluminometasilicate, magnesium aluminosilicate, synthetic aluminum silicate, dried aluminum hydroxide gel, and synthetic hydrotalcite, and even more preferably magnesium aluminometasilicate and dried aluminum hydroxide. Examples of antacids containing magnesium include magnesium aluminometasilicate, magnesium alumina hydroxide, magnesium silicate, magnesium hydroxide, magnesium oxide, magnesium carbonate, and synthetic hydrotalcite, more preferably magnesium aluminometasilicate, magnesium hydroxide, and synthetic hydrotalcite, even more preferably magnesium aluminometasilicate and magnesium hydroxide; and examples of antacids containing sodium include sodium bicarbonate.

In addition, in the oral pharmaceutical composition of the present invention, the ratio of component (A) to component (B) can be, for example, 66 to 10,000 parts by weight of component (B) in total per 100 parts by weight of component (A). From the perspective of further effectively enhancing the bitterness-reducing effect of itopride and/or a salt thereof, the total amount of component (B) per 100 parts by weight of component (A) is preferably 100 to 10,000 parts by weight, more preferably 500 to 5,000 parts by weight, even more preferably 1,000 to 4,000 parts by weight, still more preferably 1,200 to 3,500 parts by weight, even more preferably 1,500 to 3,500 parts by weight, and particularly preferably 2,000 to 3,500 parts by weight.

The content of component (B) in the oral pharmaceutical composition of the present invention may be set appropriately depending on the type, dosage form, and dosage of component (B) used, within the range corresponding to the ratio of component (A) to component (B) described above. Examples of the content include 10 to 99.9% by weight, preferably 30 to 99% by weight, more preferably 40 to 95% by weight, even more preferably 50 to 90% by weight, even more preferably 65 to 85% by weight, and particularly preferably 80 to 85% by weight.

[(C) Azulene derivative]
The oral pharmaceutical composition of the present invention can contain an azulene derivative as component (C). When itopride and/or a salt thereof is used in combination with an azulene derivative, the bitterness characteristic of itopride and/or a salt thereof can be effectively alleviated.

Azulene derivatives are known compounds that are incorporated into gastrointestinal medications as anti-inflammatory ingredients. Specifically, azulene derivatives are compounds and salts thereof in which one or more substituents are bonded to the azulene backbone. The azulene derivatives used in the present invention are not particularly limited as long as they are pharmaceutically or cosmetically acceptable. However, from the perspective of more effectively enhancing the bitterness-reducing effect of itopride and/or its salts, examples include azulene derivatives in which at least an acidic functional group is bonded to the azulene backbone. Specific examples of such acidic functional groups include sulfo groups and carboxyl groups, with sulfo groups being preferred.

Specific examples of azulene derivatives used in the present invention include azulene sulfonic acid (guaiazulene sulfonic acid), dimethylisopropylazulene (guaiazulene), dimethylethylazulene (kamaazulene), and 1,4-dimethyl-7-ethylazulene-3-sulfonic acid (kamaazulene sulfonic acid).

When the azulene derivative is in the form of a salt, the type of salt is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. Examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; other metal salts such as aluminum salt; ammonium salt; carboxylates such as acetate, trifluoroacetate, butyrate, palmitate, stearate, fumarate, maleate, succinate, malonate, lactate, tartrate, and citrate; organic sulfonates such as methanesulfonate, toluenesulfonate, and tosylate; organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, and picoline salt; and inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, and phosphate.

These azulene derivatives may be used alone or in combination of two or more.

Of these azulene derivatives, from the viewpoint of more effectively improving the bitterness and/or astringency of itopride and/or its salts, salts of azulene derivatives are preferred, specifically salts of azulene sulfonic acid and 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, more preferably alkali metal salts, alkaline earth metal salts, and other metal salts of azulene sulfonic acid and 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, even more preferably alkali metal salts of azulene sulfonic acid and 1,4-dimethyl-7-ethylazulene-3-sulfonic acid, even more preferably alkali metal salts of azulene sulfonic acid, and particularly preferably sodium azulene sulfonate.

In addition, in the oral pharmaceutical composition of the present invention, the ratio of component (A) to component (C) is, for example, 0.1 to 50 parts by weight of the total amount of component (C) per 100 parts by weight of component (A). From the perspective of further effectively enhancing the bitterness-reducing effect of itopride and/or a salt thereof, the total amount of component (C) per 100 parts by weight of component (A) is preferably 0.2 to 40 parts by weight, more preferably 0.3 to 30 parts by weight, even more preferably 0.4 to 20 parts by weight, even more preferably 0.5 to 15 parts by weight, and particularly preferably 0.8 to 4 parts by weight.

The content of component (C) in the oral pharmaceutical composition of the present invention may be set appropriately depending on the type, dosage form, and dosage of component (C) used, within the range corresponding to the ratio of component (A) to component (C) described above. Examples of the content include 0.01 to 10% by weight, preferably 0.05 to 8% by weight, more preferably 0.08 to 6% by weight, even more preferably 0.1 to 1% by weight, and even more preferably 0.15 to 0.3% by weight.

[Other ingredients]
The oral pharmaceutical composition of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned ingredients. The types of such pharmacological ingredients are not particularly limited, and examples include anti-inflammatory analgesics, digestives, antispasmodics, mucosal repair agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, hypnotics and sedatives, antihistamines, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, proton pump inhibitors, herbal medicines, herbal extracts, caffeines, menthols, polyphenols, etc. These pharmacological ingredients may be used alone or in combination of two or more. The content of these pharmacological ingredients may be appropriately determined depending on the type of pharmacological ingredient used, the dosage form of the oral pharmaceutical composition, etc.

The pharmaceutical composition of the present invention may contain pharmaceutically acceptable bases and additives, as necessary, to prepare it into the desired dosage form. Examples of such bases and additives include excipients, lubricants, disintegrants, binders, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV protection agents, preservatives, flavoring agents, fragrances, powders, thickeners, dyes, and chelating agents.

These bases and additives may be used alone or in combination of two or more. Among these bases and additives, preferred are excipients and lubricants. Preferred excipients include sugars, more preferably lactose. Preferred lubricants include stearates, more preferably magnesium stearate.

The content of these bases and additives may be appropriately determined depending on the type of additive used and the dosage form of the oral pharmaceutical composition. Preferably, the total content of the additives is, for example, 10 to 98% by weight, and preferably 12 to 35% by weight.

More specifically, the excipient content may be, for example, 5 to 98% by weight, preferably 6 to 60% by weight, and more preferably 7 to 30% by weight; the stearate content may be, for example, 0.1 to 5% by weight, preferably 0.3 to 3% by weight, more preferably 0.5 to 1% by weight, and even more preferably 0.7 to 0.9% by weight.

[Dosage form]
The dosage form of the oral pharmaceutical composition of the present invention is not particularly limited, and may be any of a solid preparation, a semi-solid preparation, or a liquid preparation.

Specific examples of solid preparations include tablets, pills, capsules (soft capsules, hard capsules), powders, granules (including dry syrup), chewable tablets, etc. Specific examples of semi-solid preparations include jellies, etc. Specific examples of liquid preparations include solutions, suspensions, syrups, etc.

The oral pharmaceutical composition of the present invention is excellent in reducing the bitterness of itopride and/or its salts, and therefore can effectively reduce the bitterness even in dosage forms that are inherently prone to bitterness. From this perspective, preferred dosage forms of the oral pharmaceutical composition of the present invention that are highly useful include powders and granules, and more preferably powders.

To prepare the oral pharmaceutical composition of the present invention in the above dosage form, component (A), component (B) and/or component (C), and optionally other pharmacological ingredients, bases, and/or additives, may be formulated according to conventional formulation techniques used in the pharmaceutical field.

[Dosage/Dosage]
The oral pharmaceutical composition of the present invention can exhibit a gastrointestinal motility activating effect based on itopride and/or a salt thereof, an antacid effect based on an antacid used to reduce bitterness, and/or an anti-inflammatory effect based on an azulene derivative used to reduce bitterness, and is therefore suitable for use as a complex gastrointestinal drug.

The dosage of the oral pharmaceutical composition of the present invention can be appropriately determined depending on the intended use, the age of the recipient, etc., but for example, it can be taken 1 to 3 times a day at a daily dosage of approximately 75 to 150 mg of itopride and/or a salt thereof, preferably approximately 100 to 150 mg.

2. Method for Reducing the Bitterness of Itopride and/or a Salt Thereof The present invention also provides a method for reducing the bitterness of itopride and/or a salt thereof, comprising comprising containing (A) itopride and/or a salt thereof in an oral pharmaceutical composition together with (B) an antacid and/or (C) an azulene derivative.

In this bitterness reduction method, the types of ingredients used, the amounts used, and the dosage form of the oral pharmaceutical composition are as described above in the section "1. Oral Pharmaceutical Composition."

3. Tablet Composition The tablet composition of the present invention is characterized by containing (A) itopride and/or a salt thereof, and (D) a methylmethionine sulfonium salt and/or (E) aluminum hydroxide. The tablet composition of the present invention is described in detail below.

[(A) Itopride and/or its salt]
The tablet composition of the present invention contains itopride and/or a salt thereof as component (A). Specific and preferred examples of (A) are as described in the section "(A) Itopride and/or a salt thereof" in "1. Oral pharmaceutical compositions" above.

The content of component (A) in the tablet composition of the present invention can be appropriately determined in principle depending on the size of the tablets to be formed, the number of tablets to be taken per dose, etc., but may be, for example, 0.1 to 90% by weight. From the perspective of further enhancing the effect of improving tablet hardness, the content of component (A) in the tablet composition of the present invention is preferably 1 to 60% by weight, more preferably 2.5 to 50% by weight, and even more preferably 4 to 40% by weight.

More specifically, when the tablet composition of the present invention contains component (D), the content of component (A) can be appropriately set depending on the size of the tablets to be formed, the number of tablets to be taken per dose, etc., but can be, for example, 30 to 90% by weight. From the viewpoint of further enhancing the effect of improving tablet hardness, the content is preferably 35 to 85% by weight, more preferably 36 to 50% by weight, and even more preferably 36 to 40% by weight.

When the tablet composition of the present invention contains component (E), the content of component (A) can be appropriately determined depending on the size of the tablets to be formed, the number of tablets to be taken per dose, etc., but may be, for example, 0.1 to 90% by weight. From the viewpoint of further enhancing the effect of improving tablet hardness, the content is preferably 1 to 30% by weight, more preferably 1.5 to 10% by weight, and even more preferably 2 to 6% by weight.

[(D) Methylmethionine sulfonium salt]
The tablet composition of the present invention may contain a methylmethionine sulfonium salt as component (D). When itopride and/or a salt thereof is used in combination with a methylmethionine sulfonium salt, the hardness of the tablet can be effectively improved.

Methionine sulfonium salts are known ingredients used in gastrointestinal medications as gastrointestinal mucosal repair ingredients. There are no particular limitations on the type of methylmethionine sulfonium salt, as long as it is pharmaceutically or cosmetically acceptable. Examples include salts of methylmethionine sulfonium with a compound selected from the group consisting of inorganic acids, organic acids, acidic amino acids, and 5'-nucleotides. Examples of inorganic acids include hydrochloric acid, sulfuric acid, and nitric acid. Examples of organic acids include citric acid, malic acid, and succinic acid. Examples of acidic amino acids include glutamic acid and aspartic acid. Examples of 5'-nucleotides include 5'-inosinic acid, 5'-adenylic acid, and 5'-guanylic acid.

These methylmethionine sulfonium salts may be used alone or in combination of two or more.

Among these methylmethionine sulfonium salts, from the viewpoint of more effectively enhancing the tablet hardness-improving effect, salts of methylmethionine sulfonium and inorganic acids are preferred, and salts of methylmethionine sulfonium and hydrochloric acid (i.e., methylmethionine sulfonium chloride) are more preferred.

The content of component (D) in the tablet composition of the present invention may be appropriately determined depending on the type, dosage form, and dosage amount of component (D) used, but may be, for example, 5 to 90% by weight, preferably 10 to 70% by weight, more preferably 20 to 60% by weight, even more preferably 30 to 50% by weight, and even more preferably 35 to 40% by weight.

In addition, the ratio of component (A) to component (D) in the tablet composition of the present invention is determined depending on the content of each of the above components, but the total amount of component (D) per 100 parts by weight of component (A) is, for example, 5 to 500 parts by weight. From the perspective of more effectively enhancing the tablet hardness-improving effect, the total amount of component (D) per 100 parts by weight of component (A) is preferably 10 to 200 parts by weight, more preferably 50 to 150 parts by weight, even more preferably 80 to 120 parts by weight, and particularly preferably 90 to 110 parts by weight.

[(E) Aluminum hydroxide]
The tablet composition of the present invention may contain aluminum hydroxide as component (E). When itopride and/or a salt thereof is used in combination with aluminum hydroxide, the hardness of the tablet can be effectively improved.

Aluminum hydroxide is a well-known ingredient used in stomach medicines as an antacid. Materials for incorporating aluminum hydroxide into the tablet composition of the present invention include, for example, aluminum hydroxide gel (e.g., dried aluminum hydroxide gel; specifically, dried aluminum hydroxide gel as defined in the Japanese Pharmacopoeia, 18th Edition, and dried aluminum hydroxide gel granules as defined in the Japanese Pharmacopoeia, 18th Edition), aluminum hydroxide/sodium bicarbonate co-precipitation product, aluminum hydroxide/magnesium carbonate mixed dry gel, and aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitation product.

These methylmethionine sulfonium salts may be used alone or in combination of two or more.

Of these aluminum hydroxide materials, from the viewpoint of more effectively enhancing the tablet hardness-improving effect, aluminum hydroxide gel is preferred, dried aluminum hydroxide gel is more preferred, and dried aluminum hydroxide gel as specified in the Japanese Pharmacopoeia, 18th Edition, and dried aluminum hydroxide gel granules as specified in the Japanese Pharmacopoeia, 18th Edition are even more preferred.

The content of component (E) in the tablet composition of the present invention may be set appropriately depending on the dosage form, dosage amount, etc., but may be, for example, 10 to 99.9% by weight, preferably 20 to 99% by weight, more preferably 40 to 95% by weight, even more preferably 60 to 95% by weight, even more preferably 80 to 95% by weight, and particularly preferably 88 to 95% by weight.

In addition, the ratio of component (A) to component (E) in the tablet composition of the present invention is determined depending on the content of each of the above components, but the total amount of component (E) per 100 parts by weight of component (A) is, for example, 400 to 5000 parts by weight. From the perspective of more effectively enhancing the tablet hardness-improving effect, the total amount of component (E) per 100 parts by weight of component (A) is preferably 1000 to 3000 parts by weight, more preferably 1500 to 2500 parts by weight, and even more preferably 1800 to 2200 parts by weight.

The content of component (E) above refers to the amount of aluminum hydroxide. For example, if the material used to incorporate component (E) contains components other than aluminum hydroxide (for example, components other than aluminum hydroxide that may be contained in dried aluminum hydroxide gel, components other than aluminum hydroxide and excipients that may be contained in dried aluminum hydroxide gel granules, coprecipitated salts other than aluminum hydroxide contained in coprecipitated products containing aluminum hydroxide, etc.), the content refers to the amount excluding such other components.

[Other ingredients]
In addition to the above-mentioned ingredients, the tablet composition of the present invention may contain other nutritional ingredients or pharmacological ingredients depending on its intended use. Such nutritional ingredients and pharmacological ingredients are not particularly limited as long as they are pharmaceutically acceptable. Examples include antacids (other than aluminum hydroxide), stomachic agents, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents (other than methylmethionine sulfonium salts), anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal extract powders, vitamins, and menthols. These nutritional ingredients and pharmacological ingredients may be used alone or in combination of two or more. The content of these ingredients is appropriately determined depending on the type of ingredients used, etc.

In addition to the above-mentioned ingredients, the tablet composition of the present invention may also contain additives necessary for tablet formulation, if necessary. Such additives are not particularly limited as long as they are pharmaceutically acceptable, and examples include water, excipients, lubricants, disintegrants, binders, antioxidants, preservatives, flavorings, flavoring agents, thickeners, dyes, pH adjusters, buffers, chelating agents, etc.

The above-mentioned additives may be used alone or in combination of two or more. Among the above-mentioned additives, the tablet composition of the present invention preferably contains an excipient, lubricant, and/or disintegrant. Preferred examples of the excipient, lubricant, and/or disintegrant include silicates (more preferably aluminum silicate, etc.), sugars (more preferably lactose, etc.), stearates (more preferably magnesium stearate, etc.), cellulose derivatives (hydroxypropyl cellulose, etc.), etc.

The content of the additives is set appropriately depending on the type of additive used. Preferably, the total content of the additives is, for example, 10 to 40% by weight, preferably 15 to 35% by weight, and more preferably 20 to 30% by weight.

More specifically, the silicate content can be, for example, 2 to 7% by weight, preferably 3 to 5.5% by weight, and more preferably 3.5 to 4.8% by weight; the sugar content can be, for example, 5 to 35% by weight, preferably 8 to 30% by weight, and more preferably 10 to 25% by weight; the stearate content can be, for example, 0.3 to 1.5% by weight, preferably 0.5 to 1.2% by weight, and more preferably 0.7 to 0.9% by weight; and the cellulose derivative content can be, for example, 2 to 7% by weight, preferably 3 to 5% by weight, and more preferably 3.5 to 4% by weight.

[Tablet hardness]
The tablet composition of the present invention, when formed into tablets, can have improved hardness compared to tablets not containing component (D) and/or component (E). The specific hardness varies depending on the composition of components other than component (A), but examples include 40 N or more, preferably 45 to 500 N, more preferably 60 to 500 N, even more preferably 80 to 500 N, even more preferably 100 to 500 N, and particularly preferably 120 to 500 N, 120 to 400 N, 120 to 300 N, 120 to 200 N, or 120 to 150 N. In the present invention, the tablet hardness refers to the value measured using a load cell tablet hardness tester.

[Dosage form]
The form of the tablet composition of the present invention includes tablets and any form intended to be formed into tablets (for example, a powder composition before granulation, a granulated product (granules) before tableting, etc.).

Furthermore, when the tablet composition of the present invention is in tablet form, the tablet may be plain, or may be coated with a sugar-coating base, a water-soluble film-coating base, or the like, as necessary.

The weight of each tablet of the present invention may be appropriately determined depending on the number of tablets to be taken per dose, the contents of component (A), component (D), component (E), and/or other components, and may be, for example, 100 to 1500 mg, preferably approximately 130 to 1200 g.

[Manufacturing method]
The tablet composition of the present invention can be obtained by a known manufacturing method, specifically by mixing the raw materials to form a powder composition, by granulating the powder composition to form granules, by granulating a portion of the raw materials to form granules and mixing them with the remaining granules of the raw materials to form a granule mixture, or by subjecting the powder composition, granules, or granule mixture to tableting.

Tableting can be carried out using equipment such as a single punch tablet press, rotary tablet press, high-speed rotary tablet press, or hydrostatic press. The tableting pressure used during tableting is not particularly limited as long as it is possible to form a tablet, but examples include approximately 5 to 20 kN, and preferably approximately 10 to 15 kN.

4. Method for Increasing Tablet Hardness The present invention also provides a method for increasing the hardness of a tablet containing itopride and/or a salt thereof, in which the tablet composition contains (A) itopride and/or a salt thereof, as well as (D) methylmethionine sulfonium salt and/or (E) aluminum hydroxide.

In this hardness-enhancing method, the types of ingredients used, their amounts, and the form of the tablet composition are as described above in "3. Tablet Composition."

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

[Test Example 1]
The ingredients shown in Table 1 were mixed to prepare powders, and 11 expert taste testers (men and women in their 20s to 40s) evaluated the taste. The ingredients shown in Table 2 were mixed to prepare powders, and 5 expert taste testers (men and women in their 20s to 40s) evaluated the taste. The tastes evaluated were bitterness (an unpleasant initial taste) and astringency (an unpleasant aftertaste). The evaluators were asked to rinse their mouths with tap water before evaluating the taste of each powder.

For taste evaluation, 2000 mg of each powder was placed in the mouth, the taste was confirmed, and then spat out, and the taste was scored according to the following criteria. The bitterness score for the powder of Comparative Example 1 was set to 1, and the relative value of the bitterness score for the powder of each Example was obtained as a bitterness improvement index. A bitterness improvement index greater than 1 can be considered to have improved the bitterness. Similarly, the astringency improvement index for the powder of Comparative Example 1 was set to 1, and the relative value of the astringency score for the powder of each Example was obtained as a bitterness improvement index. A bitterness improvement index greater than 1 can be considered to have improved the astringency. The results are shown in Table 1.

<Criteria for determining bitterness>
4 points: Not bitter at all 3 points: Not very bitter 2 points: Slightly bitter 1 point: Bitter 0 point: Very bitter

<Criteria for determining bitterness>
4 points: Not bitter at all 3 points: Not very bitter 2 points: Slightly bitter 1 point: Bitter 0 point: Very bitter

As is clear from Tables 1 and 2, the oral pharmaceutical compositions of Examples 1 to 6, in which itopride hydrochloride was combined with an antacid or an azulene derivative, were found to have an effect of alleviating the bitterness characteristic of itopride hydrochloride. Furthermore, the oral pharmaceutical compositions of Examples 2, 3, 4, and 6 were found to have an especially significant effect of alleviating unpleasant tastes, alleviating not only the bitterness but also the acrid taste characteristic of itopride hydrochloride.

[Test Example 2]
Tablets having the compositions shown in Table 3 were produced. Specifically, the components shown in Table 3 were mixed in predetermined amounts, and the resulting mixed powder composition was compressed into tablets using a static press (TB-20H-V09, NPa Systems Co., Ltd.) at a compression pressure of 10 kN (Comparative Examples 2 and 3 and Example 7) or 15 kN (Comparative Example 4 and Example 8). Disc-shaped tablets (plain tablets) each weighing 130 mg and having a diameter of 8 mm (Comparative Examples 2 and 3 and Example 7) or disc-shaped tablets (Comparative Example 4 and Example 8) weighing 1200 mg and having a diameter of 15 mm were obtained. The hardness of 10 to 11 tablets obtained from each tablet was measured using a load cell tablet hardness tester (PC-30, Okada Seiko Co., Ltd.), and the average value was calculated. The results are shown in Table 3.

As is clear from Table 3, the tablets of Examples 7 and 8, which were molded from tablet compositions containing itopride hydrochloride and methylmethionine sulfonium salt or aluminum hydroxide, had significantly improved hardness compared to the tablets of Comparative Examples 2 and 4, which did not contain methylmethionine sulfonium salt or aluminum hydroxide, respectively.

Prescription Example (I)
Oral pharmaceutical compositions were prepared according to the formulations shown in Tables 4 and 5. All oral pharmaceutical compositions were found to have the effect of improving the bitterness inherent to itopride hydrochloride.

Prescription Example (II)
Tablet compositions were prepared according to the formulations shown in Tables 7 and 8. All tablet compositions showed a significant improvement in hardness.

Claims (3)

An oral pharmaceutical composition comprising (A) itopride and/or a salt thereof, and (B) an antacid selected from the group consisting of synthetic hydrotalcite, magnesium hydroxide, magnesium aluminometasilicate, sodium bicarbonate, calcium carbonate, dihydroaluminum aminoacetate, synthetic aluminum silicate, magnesium aluminosilicate, magnesium oxide, magnesium carbonate, squid bone, and calcium hydrogen phosphate . 2. The oral pharmaceutical composition according to claim 1 , comprising a total amount of 66 to 10,000 parts by weight of component (B) per 100 parts by weight of component (A). A method for improving the bitterness of itopride and/or a salt thereof, comprising comprising, in an oral pharmaceutical composition, (A) itopride and/or a salt thereof and (B) an antacid selected from the group consisting of synthetic hydrotalcite, magnesium hydroxide, magnesium aluminometasilicate, sodium bicarbonate, calcium carbonate, dihydroaluminum aminoacetate, synthetic aluminum silicate, magnesium aluminosilicate, magnesium oxide, magnesium carbonate, squid bone, and calcium hydrogen phosphate .